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BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.
PMCID: PMC2907815

Influenza

Abstract

Introduction

During the autumn-winter months (influenza seasons), influenza circulates more frequently, causing a greater proportion of influenza-like illness, and sometimes serious seasonal epidemics. The incidence of infection depends on the underlying immunity of the population.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of vaccines to prevent influenza? What are the effects of antiviral chemoprophylaxis of influenza? What are the effects of antiviral medications to treat influenza? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: vaccines, amantadine, oseltamivir, zanamivir, rimantadine.

Key Points

Influenza viruses are constantly altering their antigenic structure, and every year the WHO recommends which strains of influenza should be included in vaccines.

  • During the autumn-winter months, influenza circulates more frequently (influenza seasons), causing a greater proportion of influenza-like illness, and sometimes serious seasonal epidemics.
  • The incidence of infection depends on the underlying immunity of the population.

When a significantly different form of influenza occurs by mutation, it can greatly increase infection rates, as well as morbidity and mortality (a pandemic).

Influenza and influenza-like illness (caused by a range of other viruses) are clinically indistinguishable.

  • Trials of vaccines assess how to prevent the symptoms and consequences of both, as well as infection rates.

Vaccines are effective in reducing infection and school absence in children over 2 years old, but there is no evidence that they reduce transmission, hospitalisation, pneumonia, or death.

Live or inactivated vaccines are effective in reducing infection and in slightly reducing absence from work in adults, but there is no evidence that they reduce transmission, hospitalisation, pneumonia, or death.

There is poor-quality evidence from cohort studies that vaccines are effective in elderly people living in institutions, but there is little good-quality evidence for the elderly population in general.

Zanamivir and oseltamivir provide symptomatic relief, or prevent symptoms if administered early in the disease, but do not prevent infection.

  • Zanamivir and oseltamivir interrupt household transmission of seasonal influenza, prevent hospitalisations, and reduce, but do not suppress, viral excretion from the nose.
  • These agents cause fewer adverse effects than amantadine and rimantadine, and there is less evidence of resistance.

Although amantadine and rimantadine provide symptomatic relief or prevent symptoms if administered early in influenza A, they engender viral resistance.

  • Amantadine and rimantadine do not prevent infection and transmission, and cause harms, especially in a prophylactic role.

Amantadine was ineffective in the 1968-1969 pandemic, and zanamivir, oseltamivir, and newer vaccines are untested in a pandemic.

Symptomatic relief with echinacea, vitamin C, and decongestants in influenza-like illness is covered in the review on the common cold.

Single studies reporting data for one or two seasons are difficult to interpret, and not easy to generalise from, because of the marked variability of viral circulation.

About this condition

Definition

Influenza is an acute respiratory illness caused by infection with influenza A and B viruses. The illness can affect both the upper and lower respiratory tract and is often accompanied by systemic signs and symptoms, such as: abrupt onset of fever; chills; non-productive cough; myalgias; headache; nasal congestion; sore throat; and fatigue. Diagnosis: Not everyone infected with influenza viruses become symptomatic, and not everyone with the above symptoms will have influenza. This is because different viral and bacterial circulating agents cause an influenza-like illness with a clinical picture each year, which is indistinguishable from influenza. Between 40% and 85% of infections with influenza result in clinical illness, depending on age and pre-existing immunity to the virus.One systematic review (search date 2004, 6 RCTs in Europe, North America, and the southern hemisphere, 7164 people) of symptoms of influenza found that, in all age groups, the likelihood of influenza was decreased by the absence of fever (OR 0.40, 95% CI 0.25 to 0.66), cough (OR 0.42, 95% CI, 0.31 to 0.57), or nasal congestion (OR 0.49, 95% CI 0.42 to 0.59). It found that, in people aged 60 or older, the probability of influenza was increased by the combination of fever, cough, and acute onset (OR 5.4, 95% CI 3.8 to 7.7), fever and cough (OR 5.0, 95% CI 3.5 to 6.9), fever alone (OR 3.8, 95% CI 2.8 to 5.0), malaise (OR 2.6, 95% CI, 2.2 to 3.1), or chills (OR, 2.6, 95% CI, 2.0 to 3.2); and also found that influenza was less likely if sneezing was present (OR, 0.47, 95% CI, 0.24 to 0.92). Although influenza is usually diagnosed clinically, genuine influenza infection can only be diagnosed with laboratory confirmation, either by culture, serological responses, or by bedside testing. The rapid bedside diagnostic tests available on the market are mainly antigen detection immunoassays and (unlike laboratory tests, such as culture or reverse transcription-polymerase chain reaction) can be carried out within 30 minutes. However, the results must be interpreted with caution. During times of low influenza viral circulation, the positive predictive value is low, leading to an increased proportion of false positive results. In times of high viral circulation, the negative predictive value is low, leading to an increased proportion of false negatives. It is also impractical to test all potential influenza cases. If a good surveillance system is in place, with quick feedback, the positive predictive value of clinical diagnosis alone (based on high fever and a cough) will be similar to the bedside test (79-87%). Population: For the purpose of this review, we have included trials that assessed both influenza-like illness and influenza, which are clinically indistinguishable, in people with no co-morbid conditions. Where appropriate, the applicability of data to influenza pandemic has been discussed.

Incidence/ Prevalence

Seasonal influenza: Circulation of seasonal influenza viruses can vary between years, seasons, and even settings. In temperate areas, seasonal influenza activity typically peaks between late December and early March in the northern hemisphere, and between May and September in the southern hemisphere. In tropical areas, there is no temporal peak in influenza activity through the year. The annual incidence of influenza varies, and depends partly on the underlying level of population immunity to circulating influenza viruses. One localised study in the USA found that serological conversion, with or without symptoms, occurred in 10-20% of people a year, with the highest infection rates in people aged under 20 years. A systematic review in people aged up to 19 years found that the average incidence of influenza was 5-10%. The proportion of people affected by circulating influenza is higher in institutions, and in and areas of overcrowding. Pandemic influenza: The incidence of symptomatic influenza depends on, among other factors, the susceptibility of the host. Occasionally, a new type of influenza virus appears, generated either by direct mutation or by reassortment of the viral genome. Because immunity to this new virus is low, it is able to behave in an aggressive way, causing morbidity and mortality on a global scale, mainly because of the body's inability to prevent the creation of a high viral load, the cytopathic effect of the new virus, and the complications in target organs, such as lungs and airways. Widespread epidemics are known as pandemics. In the 20th century, three pandemics were caused by different influenza A viral subtypes (see aetiology): in 1918-19 (H1N1), 1957 (H2N2), and 1968 (H3N2). Avian influenza: Influenza infection may also appear as a zoonotic infection, with direct spread of the avian virus to humans. In April 2003, 87 people in the Netherlands were infected with avian virus H7N7. In most cases, the only symptom was conjunctivitis. However, a 57-year-old vet dealing with veterinary public-health interventions died of acute respiratory distress. An avian virus (H5N1) has been transmitted from bird to human (and occasionally from human to human) sporadically since 1997. Such transmission has frequently taken place in situations of poor hygiene and close proximity between birds and humans.

Aetiology/ Risk factors

Viral classification: The influenza virus is composed of a protein envelope around an RNA core. On the surface of the envelope are two antigens: neuraminidase (N antigen) and haemagglutinin (H antigen). The influenza virus has a marked propensity to mutate its external antigenic composition to escape the host's immune defences. Given this extreme mutability, a classification of viral subtype A based on H and N typing has been introduced. Transmission: Influenza viruses are transmitted primarily from person to person through respiratory droplets disseminated during sneezing, coughing, and talking, and through contact with contaminated surfaces. The incubation period of influenza is 1-4 days, and infected adults are usually contagious from the day before symptom onset until 5 days after symptom onset. Pandemic influenza: Pandemics are thought to originate mostly in southern China, where ducks (the animal reservoir and breeding ground for new strains), pigs (thought to be the biological intermediate host, or "mixing vessel"), and humans live in close proximity. Pigs are considered plausible intermediate hosts because their respiratory epithelial cells have receptors for both avian (i.e. duck) and human viral haemagglutinins. Minor changes in viral antigenic configurations, known as "drift", cause local or more circumscribed epidemics.

Prognosis

The symptoms of uncomplicated influenza usually resolve within 1 week, although cough and fatigue may persist. Complications include otitis media, bacterial sinusitis, secondary bacterial pneumonia, and, less commonly, viral pneumonia, respiratory failure, and exacerbations of underlying disease. In the UK, 1.3% of people with influenza-like illness are hospitalised each year (95% CI 0.6% to 2.6%). It is estimated that 300-400 deaths each year are attributable to influenza, rising to in excess of 29,000 during an epidemic. The risk of hospitalisation is highest in people aged 65 years or older, in young children, and in people with chronic medical conditions. Over 90% of influenza-related deaths during recent seasonal epidemics in the USA have been in people aged 65 years or older. During influenza pandemics, morbidity and mortality may be high in younger age groups. Severe illness is more common with influenza A infections than with influenza B infections. For pandemic influenza, see incidence.

Aims of intervention

To prevent illness and its complications; to reduce the duration and severity of influenza symptoms, and the risk of complications; and to minimise adverse effects of treatment.

Outcomes

The effectiveness of a vaccine is often measured by its ability to prevent influenza-like illness and its consequences, which is indistinguishable from influenza and commonly presents to physicians. The causative agent is rarely isolated or documented. Studies do not divide outcomes into primary and secondary because public health campaigns have different priorities and objectives. Specific outcomes covered in this review include: Chemoprophylaxis: frequency of cases, viral transmission, reduction in mortality, hospitalisation, time off work, adverse effects. Treatment: severity and duration of symptoms; frequency and severity of complications of influenza; time taken to return to normal activities; reduction in nasal viral shedding; adverse effects of treatment.

Methods

Clinical Evidence search and appraisal June 2008. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2008, Embase 1980 to June 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the review. For interventions for prevention, propylaxsis, in children, or for influenza-like illnesses, we searched from 2000 onwards, because good systematic reviews have published in this period. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. These included: systematic reviews and RCTs in any language (at least single blinded) in laboratory-confirmed influenza, or influenza-like illness (which are clinically indistinguishable), measuring clinical efficacy (antibody responses), with a minimum number of 20 people per trial and at least 80% of them followed up. We included non-randomised evidence only when it was within an included systematic review. There was no minimum length of follow-up. The searches compared treatments with placebo or no intervention, because it is important to establish the effectiveness of vaccines for outcomes, such as death, complications, hospitalisation, and transmission, and there are no direct comparisons for antiviral agents. Exclusion criteria included: RCTs involving experimentally induced influenza, interventions with more than one active agent, and all studies described as "open", "open label", or non-blinded. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). To aid readability of the numerical data in our reviews, we round percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs.

Table
GRADE evaluation of interventions for influenza

Glossary

Adjuvant
Inert substance (e.g. aluminium salts) added to vaccines to enhance their immunogenicity (i.e. their capacity to stimulate immunity).
Cytopathic effect
Producing pathological changes in cells.
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.
Zoonotic infection
An infection communicable from animals to humans.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Notes

Common cold

Influenza vaccine to prevent community-acquired pneumonia or influenza, in review on community-acquired pneumonia

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BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Vaccines in adults

Summary

PREVENTION OF INFECTION Compared with placebo: Vaccination using WHO-recommended antigens is more effective at reducing the number of cases of influenza, but does not reduce time off work ( high-quality evidence ). Vaccination of healthcare workers and patients compared with vaccination of healthcare workers alone: Vaccination of both healthcare workers and elderly patients is more effective at reducing influenza cases ( moderate-quality evidence ). MORTALITY Vaccination of healthcare workers and patients compared with placebo: Vaccination of healthcare workers and patients is more effective at reducing mortality in elderly patients, but is not effective at reducing lower respiratory tract infections (moderate-quality evidence).

Benefits

We found two systematic reviews and one subsequent RCT.comparing vaccines versus placebo in adults.

Vaccinating healthcare workers to prevent influenza in their elderly patients:

We found one systematic review (search date 2005, 2 cluster RCTs and 1 cohort study) assessing the effect of vaccinating healthcare workers on transmission of influenza to those in their care. It found that staff vaccination significantly reduced the proportion of elderly patients with influenza-like illness only when the patients were also vaccinated; if patients were not vaccinated, there was no significant difference in influenza-like illness between healthcare worker vaccination and placebo groups. The review found that vaccinating healthcare workers significantly reduced patient deaths from pneumonia, and death from all causes, but found no significant difference in lower respiratory tract infections between groups (see table 1 ).

Table 1
Prevention of influenza in patients by vaccinating healthcare workers.

Vaccines versus placebo:

We found one systematic review (search date 2006, 38 RCTs in 66,248 people), which found that recommended vaccines (containing WHO-recommended antigens) reduced the number of cases of influenza compared with placebo. There was a relative reduction compared with placebo of 56% with recommended live aerosol matched vaccines (by 64% where matching was absent or unknown), and by 80% with recommended inactivated parenteral matched vaccines (by 50% where matching was absent or unknown). The review found that vaccination did not affect the amount of time off work.

The subsequent RCT (1247 healthy adults recruited from two community and two university sites in Michigan, USA, aged 18–46 [mean age 26.9 years], 86% white people) compared live attenuated vaccine versus trivalent inactivated vaccine versus placebo. Forty people (3%) did not complete all scheduled visits, but attrition did not differ significantly among the three groups (P = 0.39). An extra 331 people were excluded from per-protocol analyses. There were 876 (70%) participants, who were included in per-protocol analyses, and baseline characteristics were similar among the 3 groups (P = 0.97). The RCT found that that, in the 2004–2005 season, in which most circulating viruses were dissimilar to those included in the vaccine, inactivated vaccine significantly reduced laboratory-confirmed symptomatic illnesses from influenza in healthy adults compared with placebo. The RCT found no significant difference in influenza-like illness between live attenuated vaccine and placebo, although rates were lower in people receiving vaccination (see table 2 ).

Table 2
Prevention of influenza in adults with vaccines versus placebo

Harms

Vaccinating healthcare workers to prevent influenza in their elderly patients:

The systematic review gave no information on adverse effects.

Vaccines versus placebo:

The systematic review (search date 2006, 38 RCTs in 66,248 people and 8 non-randomised comparative studies on harms) found that live aerosol vaccines significantly increased sore throats and coryza compared with placebo (sore throats: 907/3569 [25%] with live aerosol vaccine v 274/1822 [15%] with placebo, RR 1.73, 95% CI 1.44 to 2.08; coryza: 1370/3140 [44%] with vaccine v 432/1642 [26%] with placebo, RR 1.56, 95% CI 1.26 to 1.94).Overall, 43% of people receiving vaccine reported the combined end point (experiencing all observed adverse effects) for local reactions, such as tenderness, soreness, erythema, or arm stiffness (1386/3233 [43%] with live aerosol vaccine v 439/1688 [26%] with placebo; RR 1.56, 95% CI 1.31 to 1.87; P less than 0.00001), whereas only 16% reported the combined end point for systemic effects (82/607 [16%] with live aerosol vaccine v 45/411 [11%] with placebo; RR 1.40, 95% CI 0.82 to 2.38; P = 0.2).

Inactivated vaccines significantly increased local tenderness, erythema, and myalgia compared with placebo (local tenderness: 1775/3556 [50%] with vaccine v 588/3277 [18%] with placebo; P less than 0.00001; RR 3.11, 95% CI 2.08 to 4.66; erythema: 260/1698 [15%] with vaccine v 80/1690 [5%] with placebo; P = 0.0002; RR 4.01, 95% CI 1.91 to 8.41; myalgia: 93/1342 [7%] with vaccination v 60/1334 [5%] with placebo; P = 0.008; RR 1.54, 95% CI 1.12 to 2.11), but not induration or arm stiffness compared with placebo. Combined local effects were significantly more common with vaccine than with placebo (1542/2775 [56%] with vaccine v 536/2396 [22%] with placebo; P less than 0.0001; RR 2.87, 95% CI 2.02 to 4.06). No other systemic effects were individually more common with inactivated vaccine than with placebo. However, the combined end point for systemic adverse effects was significantly increased (340/1461 [23%] with vaccine v 177/1142 [16%] with placebo; P = 0.04; RR 1.29, 95% CI 1.01 to 1.64).

The systematic review also reported evidence on serious and rare harms. It reported that trivalent split inactivated vaccine (TIV) caused mild oculo-respiratory syndrome (ORS; defined as bilateral conjunctivitis, facial swelling [lip, lid, or mouth], difficulty in breathing and chest discomfort [including cough, wheeze, dysphagia or sore throat]) in people with no previous history of ORS. ORS (attributable risk 2.9%, 95% CI 0.6 to 5.2), hoarseness (1.3%, 95% CI 0.3 to 1.3) and coughing (1.2%, 95% CI 0.2 to 1.6) occurred within 6 days of vaccination. The association did not seem specific for any type of TIV. Based on three large non-randomised studies, the review concluded that there may be a small additional risk of Guillan–Barrè syndrome.

The subsequent RCT found that inactivated vaccine significantly increased arm stiffness compared with placebo (270/501 [54%] with vaccine v 20/99 [20%] with placebo; P less than 0.001). It also found that live attenuated vaccine significantly increased runny nose or congestion, cough, headache, and muscle aches compared with placebo (runny nose or congestion: 247/506 [49%] with live attenuated vaccine v 30/99 [30%] with placebo; P = 0.001; cough: 92/506 [18%] v 8/99 [8%]; P = 0.01; headache: 192/506 [38%] v 25/99 [25%]; P = 0.02; muscle aches: 67/506 [13%] v 5/99 [5%]; P = 0.02).

Comment

Vaccines versus placebo:

The studies in the systematic review demonstrated the danger of commencing a large vaccination campaign without adequate harms assessment. Based on two case control studies, there is no evidence of an association between influenza vaccine and demyelinating disease. Based on two studies from Switzerland, Bell's Palsy was associated with the intranasal administration of virosomal influenza within 1 to 91 days after vaccination. On this basis, the vaccine was withdrawn. The review also reported no association between vaccination and cutaneous melanoma (one study and primary cardiac arrest, but both studies had weak methods).

Influenza pandemic:

The systematic review comparing vaccines versus placebo performed a subgroup analysis of five trials carried out during the 1968–1969 pandemic. It found that old whole virion vaccines reduced the proportion of people with influenza-like illness compared with placebo (5 RCTs, 107/2790 [4%] v 169/1790 [10%]; P less than 0.00001; RR 0.35, 95% CI 0.25 to 0.48), and was highly effective against influenza, although this observation was based on a single trial (1 RCT, 2/881 [0.2%] v 32/1042 [3%]; P = 0.0003; RR 0.07, 95% CI 0.02 to 0.31). There is no evidence that more modern vaccines (spilt virion or live attenuated) are effective against pandemic influenza or its complications. Testing of “pandemic vaccines” (i.e. pre-pandemic testing) has to rely on surrogate outcomes, such as antibody titre responses, which may or may not reflect protection against a pandemic virus. The only vaccines for which there is evidence of effectiveness are the whole virion vaccine tested during the 1968–1969 pandemic and, in a smaller measure, the polyvalent vaccine tested during the same pandemic. In this case, a greater proportion of influenza-like illness cases would have been caused by the (pandemic) influenza virus. The vaccine significantly reduced the number of cases of influenza-like illness in this population by 64%. In this case, efficacy and effectiveness of the vaccine are likely to have been closer than they are during seasonal influenza outbreaks. Vaccination during a pandemic is aimed at interruption of transmission and prevention of complications, but, most important, at prevention of morbidity among those engaged in delivering essential services. To date, we have no other field proof that vaccination may ameliorate the ravages of a pandemic.

Clinical guide:

Influenza viruses are constantly altering their antigenic structure (haemagglutinins [H] and neuraminidases [N]). Every year, the WHO recommends which strains of influenza should be included in vaccines. This arrangement works well for healthy adults, in whom vaccines matching the seasonal viral antigens have superior performance to those that do not. The findings of the review in healthcare workers must be interpreted in the light of likely selection, performance, attrition, and detection biases in the included studies.

Substantive changes

No new evidence

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Vaccines in children

Summary

PREVENTION OF INFECTION Live attenuated vaccines compared with placebo: Live attenuated vaccines are more effective at reducing influenza or influenza-like illness in children aged under 16 years ( moderate-quality evidence ). Inactivated vaccines compared with placebo: Inactivated vaccines are more effective at preventing influenza infections and influenza-like illness in children ageed under 16 years (moderate-quality evidence). Inactivated vaccines compared with placebo: Innactivated vaccines are no more effective than no vaccine at reducing influenza in children aged under 2 years (moderate-quality-evidence). SCHOOL ABSENCES Inactivated vaccines compared with no vaccination: Inactivated vaccines against influenza are more effective at reducing school absences of 4 days or more in children (moderate-quality evidence).

Benefits

Vaccines versus placebo:

We found one systematic review (search date 2007, 16 RCTS and 18 cohort studies, in children age 6 months to 16 years with laboratory-confirmed influenza or influenza-type ilness) vaccination versus placebo or no vaccination. The review found that live vaccines or inactive vaccines significantly increased the prevention of confirmed influenza and influenza-like illnesses (see table 3 ). However, the review found no significant difference in prevention of confirmed influenza between inactive vaccines and no vaccine in children aged under 2 years (see table 3 ). The review also found that both one- and two-dose schedules of vaccine significantly decreased the risk of confirmed influenza compared with placebo (see table 3 ).

Table 3
Prevention of influenza in children with vaccines versus placebo

Complications in healthy children:

The systematic review found that vaccines significantly reduced school absences compared with placebo (see table 3 ). Studies assessing the effects of vaccines against secondary cases, lower respiratory tract disease, acute otitis media, and socioeconomic impact, found no significant difference between vaccines and placebo or standard care, but may have been underpowered to detect a clinically important difference.

Harms

The review was unable to reach any conclusions about adverse effects because of the heterogeneity in the presentation of harmful outcomes in the included studies.

We found one subsequent placebo-controlled RCT (1616 people of all ages) assessing harms of cold-adapted influenza vaccine–trivalent (CAIV-T; in 59 children aged 6 to less than 16 weeks, and 61 children aged 16 to less than 24 weeks).The RCT found that, compared wtih placebo, two doses of CAIV-T significantly increased the incidence of runny nose or nasal discharge in children aged less than 24 weeks (81% with CAIV-T v 75% with placebo; P = 0.035, absolute numbers not reported).

Comment

The 2008 update of the systematic review reported that included studies were of poor quality, with extensive evidence of reporting bias and inconsistencies between text and data tables. The data presented in this option should be interpreted with care.

Clinical guide:

Influenza viruses are constantly altering their antigenic structure (haemagglutinins [H] and neuraminidases [N]). Every year, the WHO recommends which strains of influenza should be included in vaccines. The limited evidence on the effects of influenza vaccines in children under 2 years suggests no significant difference from placebo. There is no evidence on the effects of vaccination of children in a pandemic.

Substantive changes

Vaccines in children One systematic review added comparing live or inactive vaccine versus placebo or no vaccine.The review found that live or inactive vaccination significantly reduced the risk of laboratory-confirmed influenza or influenza-like illness in children up to 16 years. However, the review reported no significant difference in prevention of laboratory-confirmed influenza for children aged under 2 years between inactive vaccine and placebo. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Vaccines in the elderly

Summary

PREVENTION OF INFECTION Vaccination compared with no vaccination in closed communities: Vaccination of elderly people in closed communities, such as nursing homes, may be more effective at reducing influenza-like illness, but not influenza ( low-quality evidence ). Vaccination compared with no vaccination in community dwellers: Vaccination is no more effective at preventing influenza, influenza-like illness, or pneumonia, in community dwellers ( moderate-quality evidence ). Vaccination of patients and healthcare workers compared with vaccination of patients alone: Vaccination of patients and healthcare workers is more effective at reducing influenza or influenza-like illness (moderate-quality evidence). MORTALITY Vaccination compared with no vaccination in closed communities: Vaccination of elderly people with well-matched vaccines in closed communities, such as nursing homes, may be more effective at reducing pneumonia rates and mortality (low-quality evidence). Vaccination compared with no vaccination in community dwellers: Vaccination of community dwellers with well-matched vaccines is more effective at reducing mortality (moderate-quality evidence). Vaccination of patients and healthcare workers compared with placebo: Vaccination of patients and healthcare workers is more effective at reducing mortality in elderly patients, but does not reduce respiratory tract infections (moderate-quality evidence).

Benefits

We found one systematic review (searches up to 2006, 49 cohort studies reporting data for 79 influenza seasons or settings, 10 case control studies [12 seasons or settings], and 5 RCTs).

Closed communities:

The review found that in closed communities, such as nursing homes (in situations of good vaccine match and high viral circulation), inactivated split vaccines significantly reduced the proportion of people who developed influenza-like illness (by 23%), but not influenza, compared with no intervention. This result is contradictory, and the most likely explanation is selection bias in the cohorts.In addition, compared with no intervention, well-matched vaccines significantly reduced pneumonia by 46%, hospitalisation for pneumonia by 45%, deaths caused by influenza or pneumonia by 42%, and all-cause mortality by 60% (see table 4 ). Some of these studies were carried out during a low viral circulation and give higher estimates of effect, which may be due to poor study quality.

Table 4
Prevention of influenza in the institutionalised elderly with vaccines versus placebo

Community dwellers:

The systematic review (20 cohort studies) found no significant difference between vaccination and no intervention in the proportion of community dwellers who developed influenza-like illness, influenza, or pneumonia. It found that, compared with no intervention, well-matched vaccines reduced the proportion of people hospitalised for influenza, pneumonia, or cardiac disease (by 26%), and all-cause mortality by 41%. After adjustment for confounders, vaccine performance compared with no intervention improved even further for all three outcomes (see table 5 ). Newer vaccines with adjuvants significantly reduced the proportion of people with influenza-like illness (by 70%) compared with no intervention, but not hospitalisations or all-cause mortality (see table 6 ).

Table 5
Prevention of influenza among the elderly community with vaccines versus placebo
Table 6
Prevention of influenza among the elderly community with virosomal vaccines versus placebo

Universal vaccination of children:

We found one systematic review (searches up to January 2004, 6 RCTs, 2 observational studies, 3 community intervention studies, and 3 economic evaluations) of the effects on family contacts (e.g. the elderly) of universal vaccination of children. The reviewers concluded that, although the evidence is suggestive of indirect protection of contacts, it is of insufficient quality to draw firm conclusions.

Vaccination of healthcare workers:

See vaccinating healthcare workers to prevent influenza in their elderly patients, under benefits of vaccines in adults.

Harms

The review gave no information on adverse effects.

Vaccination of healthcare workers:

See vaccinating healthcare workers to prevent influenza in their elderly patients, under harms of vaccines in adults.

Comment

Clinical guide:

Influenza viruses are constantly altering their antigenic structure (haemagglutinins [H] and neuraminidases [N]). Every year, the WHO recommends which strains of influenza should be included in vaccines. In long-term care facilities, vaccines have little impact on cases of influenza, but have greater impact on influenza-like illness. However, the performance of vaccines in the community is modest, regardless of whether systematic differences between vaccinated and unvaccinated groups have been adjusted for, possibly because of the diluting effect of other agents circulating in the community, or the difficulty of vaccinating those who most need it. The contradictory nature of the evidence included in the review (mostly from non-randomised comparative studies) can be explained by the poor-quality methods, with a high probability of selection bias and confounding leading to an overestimation of the effects of the vaccines and contradictory effects. The presence of confounding by indication has now been confirmed by several empirical studies:

Simonsen L, Taylor RJ, Viboud C, et al. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infect Dis 2007;7:658–666.

Jackson LA, Jackson ML, Nelson JC, et al. Evidence of bias in estimates of influenza vaccine effectiveness in seniors. Int J Epidemiol 2006;35:337–344.

Eurich DT, Marrie TJ, Johnstone J, et al. Mortality Reduction with Influenza Vaccine in Patients with Pneumonia Outside “Flu” Season: Pleiotropic Benefits or Residual Confounding? Am J Respir Crit Care Med 2008;178:527–533. Published on 12 June 2008 as doi:10.1164/rccm.200802-282OC.

Substantive changes

No new evidence

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Oseltamivir (oral) chemoprophylaxis

Summary

PREVENTION OF SYMPTOMS Compared with placebo: Oseltamivir is more effective at preventing symptoms of influenza A and B in cases of influenza, but not in influenza-like illness ( high-quality evidence ). PREVENTION OF INFECTION Compared with placebo: Post-exposure prophylaxis with oseltamivir may be more effective at reducing symptomatic influenza in households and contacts ( low-quality evidence ). ADVERSE EFFECTS Oseltamivir has been associated with nausea, and may lead to self-injury and delirium.

Benefits

We found one systematic review (search date 2005, 2 RCTs, 1867 otherwise healthy people) comparing oral oseltamivir prophylaxis versus placebo for influenza A and B. It found that, compared with placebo, oseltamivir (75 mg or 150 mg daily) was more effective at preventing symptoms in cases of influenza, but not in cases of influenza-like illness (see table 7 ). It found no significant difference in rates of influenza infection between oseltamivir 75 mg or 150 mg daily and placebo (see table 8 ).

Table 7
Prevention of symptoms with prophylactic antiviral treatment versus placebo
Table 8
Prevention of infection with prophylactic antiviral treatment versus placebo

Post-exposure prophylaxis:

The review identified two RCTs, which randomised contacts to receive treatment once a household member had reported influenza-like illness symptoms (index case). The first RCT (812 healthy, non-pregnant contacts, cluster-randomised during a documented community influenza outbreak) compared post-exposure prophylaxis with oseltamivir (given within 48 hours of index case presenting) for 10 days versus treatment at the time of developing illness (expectant treatment) in household contacts of individuals presenting with influenza-like illness (298 index cases). All index cases received oseltamivir treatment twice daily for 5 days. Children aged under 1 year were excluded. It found that both treatments significantly reduced cases of symptomatic influenza by 59% (95% CI 15.6% to 79.6%) for households and 68% (95% CI 34.9% to 84.2%) for individual contacts compared with placebo (between-group significance not assessed). The second RCT (377 index cases, 374 households, 962 healthy contacts, with a mean age of 33 years, between 2–8 members/household) compared 75 mg oseltamivir (given within 48 hours of index case presenting) for 7 days and 500 mg acetaminophen, if needed, versus placebo. Index cases were not treated. It found that, compared with placebo, oseltamivir significantly reduced cases of symptomatic influenza, by 89% (95% CI 67% to 97%) in individuals and by 84% (95% CI 45% to 95%) in households. Neither trial reported the onset of viral resistance after 5–7 days of prophylaxis at a dose of 75 mg either once or twice daily (absolute figures not reported for either RCT).

Harms

The systematic review found that oseltamivir increased the proportion of people with nausea compared with placebo (OR 1.79, 95% CI 1.10 to 2.93), especially at the higher prophylactic dose of 150 mg daily (OR 2.29, 95% CI 1.34 to 3.92).

Drug safety alert:

A drug safety alert has been issued on self-injury and delirium associated with oseltamivir (www.fda.gov/medwatch).

Comment

Clinical guide:

Oseltamivir prevents influenza symptoms, but not those caused by other agents not clinically distinguishable from influenza. Therefore, routine administration of oseltamivir when influenza is undiagnosed, or its local circulation is unknown, is unlikely to be beneficial and may engender resistance, harms, and high costs. We have no evidence of the use of oseltamivir in a pandemic, as it was not developed at the time of the last pandemic. Similarly, the drug has never been administered to people with avian influenza (H5N1 type) within a trial.

Substantive changes

No new evidence

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Zanamivir (orally inhaled) chemoprophylaxis

Summary

PREVENTION OF SYMPTOMS Compared with placebo: Orally inhaled zanamivir is more effective at preventing symptoms of influenza, but not of influenza-like illness ( high-quality evidence ). PREVENTION OF INFECTION Compared with placebo: Post-exposure prophylaxis with zanamivir is more effective at reducing the duration and proportion of cases of symptomatic influenza and influenza-like illness in households and in individuals ( moderate-quality evidence ).

Benefits

We found one systematic review (search date 2005, 2 RCTs, 699 otherwise healthy people) comparing orally inhaled zanamivir prophylaxis with placebo for influenza A and B. It found that, compared with placebo, zanamivir 10 mg daily increased prevention of symptoms in people with influenza infection, but not with influenza-like illness (see table 7 ). It found no significant difference in rates of influenza infection between zanamivir and placebo (see table 8 ).

Post-exposure prophylaxis:

The review identified two RCTs, which randomised contacts to receive treatment or placebo once a household member had reported influenza-like illness symptoms (index case). The first RCT found that 10 mg of orally inhaled zanamivir significantly reduced symptomatic infection by 81% (95% CI 64% to 90%) in households and by 82% in individuals, and influenza-like illness by 79% (95% CI 64% to 90%) in households. Zanamivir significantly reduced the duration of illness by 1.5 days, was well tolerated, and the RCT reported no viral resistance.

The second RCT found that zanamivir significantly reduced influenza, by 79% (95% CI 57% to 89%), and influenza-like illness by 72% (95% CI 42% to 87%) in contacts compared with placebo. Zanamivir also shortened the duration of symptoms by 2.5 days. There was no evidence of the onset of resistance (absolute figures not reported for either RCT).

We found one additional poorly reported post-exposure prophylaxis multicentre RCT (889 long-term facility residents) carried out over one to three seasons, comparing prophylactic zanamivir (inhaled 10 mg/day) for 14 days versus placebo. A high proportion of residents had comorbidities (e.g. 63% had a chronic respiratory condition). The RCT found no significant difference in prevention of confirmed cases of influenza or in symptomatic influenza confirmed by culture for zanamivir compared with placebo (confirmed cases: 15/240 [6%] with zanamivir v 23/249 [9%] with placebo; P = 0.355; protective efficacy for zanamivir = 29%, 95% CI 31% to 62%; symptomatic influenza confirmed by culture: 5/240 [2%] with zanamivir v 15/249 [6%] with placebo; P = 0.052; protective efficacy = 65%, 95% CI 8.5% to 86.0%). However, the RCT found that zanamivir siginificantly reduced the risk of laboratory-confirmed influenza with fever (4/240 [2%] with zanamivir v 14/249 [6%] with placebo, 70% reduction, 95% CI 13% to 89%, P = 0.043). Owing to inconsistencies and poor reporting of this RCT, the results should be interpreted with caution.

Harms

The review gave no information about adverse effects. The additional RCT reported no significant differences for adverse effects for zanamivir (12/240 [5%] with zanamivir v 16/249 [6%] with placebo; 21% efficacy, 95% CI –63% to +62%; P = 0.653). The additional trial reported no difference between zanamivir versus placebo for any of the harms tested.

Comment

Clinical guide:

Zanamivir prevents influenza symptoms, but not those caused by other agents not distinguishable clinically from influenza. Therefore, routine administration of zanamivir when influenza is undiagnosed, or its local circulation is unknown, is unlikely to be beneficial and may engender resistance, harms, and high costs. We have no evidence of the use of zanamivir in a pandemic, because it had not been developed at the time of the last pandemic. Similarly, it has never been administered to people with avian influenza (H5N1 type) within a trial.

Substantive changes

Zanamivir (orally inhaled) chemoprophylaxis One RCT added comparing prophylactic zanamivir versus placebo. The RCT found no significant difference between groups for confirmed cases of influenza. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Amantadine (oral ) chemoprophylaxis

Summary

PREVENTION OF SYMPTOMS Compared with placebo: Amantadine is more effective at preventing symptoms of influenza and influenza-like illness in adults ( high-quality evidence ). PREVENTION OF INFECTION Compared with placebo: Amantadine is no more effective at preventing influenza in adults (high-quality evidence). ADVERSE EFFECTS Amantadine has been associated with insomnia, hallucinations, and agitation. NOTE There is consensus that amantadine should not be used for first-line chemoprophylaxis, because resistance to amantadine is high and it is only effective against influenza A. We found no direct information about amantadine for prophylaxis of influenza in elderly people, pregnant women, or children.

Benefits

We found two systematic reviews comparing oral amantadine for chemoprophylaxis of influenza in otherwise healthy people. The systematic reviews found no RCTs of amantadine for the treatment of influenza A in people aged over 65 years, in pregnant women, in people with chronic disease, or in immunised people.

Adults:

The first systematic review (search date 2005, 11 RCTs, 17,496 otherwise healthy adults) compared oral amantadine prophylaxis versus placebo for influenza A. It found that amantadine significantly reduced symptoms of influenza and influenza-like illness, but had no effect on the proportion of people infected with influenza A (see table 7 and table 8 ).

Children and elderly people:

The second systematic review compared amantadine versus placebo in people aged up to 18 years (search date 2007, 2 RCTs, 741 people) and elderly people (search date July 2007, the review found no RCTs).All of the studies were of poor quality, and were not pooled because of heterogeneity of dosage, population, and follow-up. They are not reported further here.

Harms

The review found that amantadine significantly increased insomnia, hallucinations, and agitation compared with placebo (33/1454 [2%] v 6/664 [1%], OR 4.04, 95% CI 1.64 to 9.99).The second review did not report harms by prophylaxis or treatment in children or the elderly.

Comment

Effects in a pandemic:

The first review found no significant difference between amantadine and placebo in preventing symptoms of influenza in the 1968–1969 pandemic (2605 people, RR 0.39, 95% CI 0.12 to 1.25 for influenza; and 14,021 people, RR 0.86, 95% CI 0.73 to 1.03 for influenza-like illness). It is unclear whether data from the 1968–1969 pandemic can be generalised to any future pandemic.

Clinical guide:

Despite providing symptom relief, amantadine does not prevent infection or nasal shedding, and is unlikely to interrupt transmission. It causes neurological harms and its widespread use may engender viral resistance. Its prophylactic use should be discouraged.

Substantive changes

Amantadine (oral) chemoprophylaxis One systematic review added comparing amantadine versus placebo in people aged up to 18 years, and in elderly people.None of the RCTs included in the review met our inclusion criteria. Amantadine has been associated with insomnia, hallucinations, and agitation. There is also consensus that amantadine should not be used for first-line chemoprophylaxis, because resistance to amantadine is high and it is only effective against influenza A. Categorisation changed (from Likely to be ineffective or harmful to Trade-off between benefits and harms).

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Rimantadine (oral) chemoprophylaxis

Summary

PREVENTION OF SYMPTOMS Compared with placebo: Rimantadine is no more effective at preventing symptoms of influenza A ( high-quality evidence ). PREVENTION OF INFECTION Compared with placebo: Rimantadine is no more effective at preventing infection with influenza A in children, adults, or elderly people (high-quality evidence). NOTE We found no direct information about rimantadine in the treatment of influenza in pregnant women. Rimantadine causes more adverse effects compared with placebo.

Benefits

Adults:

We found one systematic review (search date 2005, 3 RCTs, 688 otherwise healthy people), comparing oral rimantadine prophylaxis versus placebo for influenza A. The review found no significant difference between rimantadine and placebo in the prevention of symptoms or infection with influenza A (see table 7 and table 8 ).

Children and the elderly:

We found one systematic review (search date July 2007, 2 RCTs in elderly people, 103 people; 3 RCTs in children, 178 people) comparing oral rimantadine prophylaxis versus placebo. The review found no significant difference between rimantadine prophylaxis and placebo for cases of influenza A in children (RR 0.49; 95% CI 0.21 to 1.15, absolute numbers and P value not reported) or elderly people (RR 0.45, 6/72 v 5/31, 95% CI 0.14 to 1.41; P value not reported).

Harms

The first review found that, compared with placebo, rimantadine significantly increased gastrointestinal adverse effects in adults (166/177 [94%] with rimantadine v 4/180 [2%] with placebo; OR 4.39, 95% CI 1.43 to 13.52) and total adverse effects (52/279 [19%] v 30/279 [11%]; OR 1.96, 95% CI 1.19 to 3.22). Neither category of adverse effects was more specifically defined.The second review reported that rimantadine was associated with a series of harms in children and elderly people, such as tinnitus, hyperactivity, diarrhoea, and dizziness, but did not break the risks down by prophylaxis or treatment.

Substantive changes

Rimanadine (oral) chemoprophylaxis One systematic review added comparing oral rimantadine prophylaxis versus placebo in children and in elderly people. It found no significant difference between groups for cases of influenza A in children or in elderly people. Categorisation unchanged (Likely to be ineffective or harmful).

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Oseltamivir (oral) to treat influenza

Summary

DURATION OF SYMPTOMS Compared with placebo: Oral oseltamivir is more effective at reducing the duration of influenza symptoms in children aged up to 12 years, but increases vomiting ( moderate-quality evidence ). TIME TO RETURN TO NORMAL ACTIVITIES Compared with placebo: Oral oseltamivir is more effective at alleviating symptoms and at reducing the time taken to return to normal activities ( high-quality evidence ). PREVENTION OF COMPLICATIONS Compared with placebo: Oseltamivir is more effective at 28 days at reducing otitis media in children, and at reducing lower respiratory tract complications, bronchitis, and pneumonia in adults with influenza, but not with influenza-like illness (high-quality evidence). ADVERSE EFFECTS Oseltamivir may be associated with self-injury and delirium.

Benefits

We found two systematic reviews comparing oseltamivir versus placebo.

Children:

The second systematic review (search date 2005, 3 RCTs) comparing oseltamivir versus placebo in previously healthy children aged up to 12 years found that oseltamivir significantly reduced the median duration of laboratory-confirmed influenza by 26% (36 hours) and influenza-like illness by 17% (21 hours), and the time to return to normal activity in those with influenza-like illness by 40% (44.6 hours) (see table 9 and table 10 ). It also found that oseltamivir significantly reduced the proportion of children with otitis media at 28 days (see table 11 ).

Table 9
Time to alleviation of symptoms with antiviral treatments versus placebo
Table 10
Time to return to normal activities with antiviral treatments versus placebo
Table 11
Prevention of complications with antiviral treatments versus placebo).

Adults:

The first systematic review (search date 2005, 3 RCTs, 1797 people) compared inhaled oseltamivir (usually started within 48 hours of symptom onset) versus placebo. It found that, compared with placebo, oseltamivir significantly increased the proportion of people with influenza or influenza-like illness who had alleviation of symptoms (within a given period, not specified in the review), and reduced time to return to normal activities (see table 10 ). It also found that oseltamivir significantly reduced the proportion of people with influenza, but not influenza-like illness, who developed bronchitis, all lower respiratory tract complications, or pneumonia (see table 11 ). A meta-analysis of oseltamivir and zanamivir found that both treatments reduced, but did not completely suppress, nasal excretion of influenza virus at 24 and 48 hours after randomisation (see table 12 ).

Table 12
Reduction in nasal viral shedding with antiviral treatments versus placebo

Harms

Children:

The second systematic review found that oseltamivir increased the proportion of children with vomiting (76/514 [15%] v 48/515 [9%]; OR 1.68, 95% CI 1.15 to 2.47).

Adults:

The first systematic review found that adverse effects were similar in adults taking oseltamivir compared with placebo (for example, headache: 119/134 [89%] with oseltamivir v 124/139 [89%] with placebo; OR 0.86, 95% CI 0.45 to 2.95).

Drug safety alert:

An FDA drug safety alert has been issued on self-injury and delirium associated with oseltamivir (www.fda.gov/medwatch). A review of 80 cases from literature and an in-depth review of 8 clinical cases carried out in Japan by the Japanese Institute of Pharmacovigilance on behalf of the Japanese government concluded that oseltamivir induces abnormal behaviour in adolescents and adults. This is probably due to its central nervous system suppressive action. Although the case series included several cases of sudden death and suicide, it was not possible to calculate an incidence of such harms. Recently, resistance of H1N1 viruses to oseltamivir has been reported from 59/437 (14%) isolates fron nine European countries. Given the highly selective nature of the isolates, it is not possible to generalise from the data. However the onset of resistance is a further reason against the routine use of neuraminidase inhibitors.

Comment

The trials included in the second review found no evidence of resistance. However, the discussion of the systematic review cited reports of resistance, especially in young children.

Clinical guide:

All trials included in the systematic review were in people who had influenza infection confirmed by laboratory findings, or reporting symptoms within 48 hours of symptom onset. It is questionable whether such evidence is relevant to everyday practice, when patients present with influenza-like illness symptoms of variable duration, possibly caused by many different agents. However, the effectiveness of oseltamivir in the intention-to-treat population would suggest effectiveness when influenza is known to have a high local circulation. In adults, oseltamivir is well tolerated. However, in children, the risk of vomiting should be weighed against the likely benefits of oseltamivir administration. We do not know whether oseltamivir would work in a pandemic or against avian influenza of the H5N1 type. Although its properties would suggest a beneficial effect, pandemic viral load and excretion are increased considerably.

Substantive changes

No new evidence

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Zanamivir (orally inhaled) to treat influenza

Summary

DURATION OF SYMPTOMS C ompared with placebo: Orally inhaled zanamivir is more effective at reducing the duration of influenza and influenza-like symptoms in adults and in children up to12 years of age ( moderate-quality evidence ). TIME TO RETURN TO NORMAL ACTIVITIES Compared with placebo: Zanamavir may be more effective at reducing the time taken to alleviate symptoms and return to normal activities ( low-quality evidence ). PREVENTION OF COMPLICATIONS Compared with placebo: Zanamavir may be more effective at preventing complications in people with influenza-like symptoms (low-quality evidence). NOTE We found no direct information about orally inhaled zanamivir in the treatment of elderly people with influenza.

Benefits

We found two systematic reviews comparing zanamivir versus placebo.

Children:

The first systematic review (search date 2005, 1 RCT)found that zanamivir significantly reduced the median duration of influenza-like illness by 10% (0.5 days) and of influenza by 24% (1.25 days) compared with placebo (see table 9 ). It also found that zanamivir significantly reduced the median time to return to normal activity by 1 day compared with placebo, although it was unclear whether this result referred to influenza-like illness or influenza (see table 10 ).

Adults:

The second systematic review (search date 2005, 8 RCTs) compared inhaled zanamivir versus placebo. It found that zanamavir significantly increased the rate of symptom alleviation and return to normal activity in both influenza-like illness and influenza, although this did not quite reach significance for return to normal activity in influenza (see table 9 and table 10 ). Zanamivir also significantly reduced complications in people with influenza-like illness, although this was only in one study, and the types of complication were not defined (see table 11 ). A pooled analysis of oseltamivir and zanamivir found that both treatments reduced, but did not completely suppress, nasal excretion of influenza virus at 24 and 48 hours after randomisation (see table 12 ).

Harms

There was no significant difference between zanamivir and placebo in the proportion of people with mild adverse effects (e.g. headache: 16/891 [2%] with zanamivir v 9/461 [2%] with placebo; OR 0.87, 95% CI 0.39 to 1.97).

Comment

Zanamivir is administered as an orally inhaled powder. In vitro studies have found that zanamivir has antiviral activity against both influenza A and B viruses. The trials included in this review and studies cited in the discussion found no evidence of resistance; however, this may reflect its limited worldwide use.

Clinical guide:

All trials included in the systematic review were in people who had influenza infection confirmed by laboratory findings, or who reported symptoms within 48 hours of symptom onset. It is questionable whether such evidence is relevant to everyday practice, when patients present with influenza-like illness symptoms of variable duration, possibly caused by various different agents. However, the effectiveness of zanamivir in the intention-to-treat population would suggest effectiveness when influenza is known to have a high local circulation. We do not know whether zanamivir would be beneficial in a pandemic. Although the properties of zanamivir would suggest a beneficial effect, pandemic viral load and excretion are increased considerably.

Substantive changes

No new evidence

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Amantadine (oral) to treat influenza

Summary

DURATION OF SYMPTOMS Compared with placebo: Oral amantadine may be more effective at reducing the duration of fever by about 1 day in adults with influenza A, but may be no more effective at reducing viral shedding from the nose at 2–5 days, and no more effective at reducing the occurrence of fever at day 3 in children ( very low-quality evidence ). ADVERSE EFFECTS Amantadine has been associated with adverse effects such as insomnia, hallucinations, and agitation. NOTE There is consensus that amantadine should not be used as first-line treatment, because resistance to amantadine is high, and it is only effective against influenza A.

Benefits

Oral amantadine versus placebo:

We found two systematic reviews. The first systematic review (search date 2007, 2 RCTs, 104 people) compared oral amantadine versus placebo in people aged up to 18 years and in elderly people.The review found no significant protective effect for amantadine compared with placebo in children (age ranges not reported) in the occurrence of fever on day 3 of treatment (2 RCTs, 104 people, 4/51 [8%] with amantadine v 12/53 [23%] with placebo, RR 0.37; 95% CI 0.08 to 1.75, absolute numbers and P value not reported). The review found no RCTs in elderly people.

The second systematic review (search date 2005, 10 RCTs, 542 people) found that amantadine significantly reduced duration of fever and length of hospital stay compared with placebo, but found no significant difference in nasal viral shedding at 2–5 days from start of treatment (see table 9 , table 10 , and table 12 ). We found no RCTs examining the effect of amantadine in preventing serious complications of influenza, such as pneumonia, exacerbation of chronic diseases, or complications in pregnancy.

The limited evidence from elderly people and from children makes it difficult to generalise results to these populations.

Harms

Oral amantadine versus placebo:

The first review reported that amantadine is associated with adverse effects such as tinnitus, hyperactivity, diarrhoea, and dizziness in children and elderly people. However, the review did not separate results between treatment and prophylaxis.

The second review found no significant difference in the frequency of adverse effects between amantadine and placebo. However, the RCTs included contained little information about the relative adverse effects of amantadine compared with placebo when used for the treatment of influenza A; and heterogeneity of outcome definitions and reporting hindered meta-analysis (see also harms of amantadine for prophylaxis).

Comment

The RCTs used different outcome measures, making it difficult to summarise the results. In vitro studies have found that amantadine has specific antiviral activity against influenza A but not influenza B viruses. All RCTs considered people with laboratory-confirmed influenza A alone, and the analyses were not by intention to treat. The proportion of influenza A isolates from the general population exhibiting resistance to amantadine is very high, and some viral strains (H5N1) are resistant.

Effects in a pandemic:

The second review identified four trials carried out during the 1968–1969 pandemic (302 people). A separate analysis of these found no significant difference in relief of symptoms, duration of hospital stay, and nasal viral shedding between a pandemic and non-pandemic population (absolute figures not reported, reported as not significant). There is insufficient evidence to comment on the effects of amantadine in a pandemic or serious epidemic scenario, but its inability to diminish or suppress nasal excretion of viruses raises serious doubts as to its ability to suppress transmission.

Clinical guide:

All trials included in the second systematic review were in people reporting and starting treatment within 48 hours of symptom onset who had influenza infection confirmed by laboratory findings. It is questionable whether such evidence is relevant to everyday practice, when patients present with influenza-like illness symptoms of variable duration, possibly caused by various different agents.

Substantive changes

Amantadine (oral) to treat influenza One systematic review added comparing amantadine versus placebo for the treatment of influenza A in children and elderly people. The review found no significant protective effect for amantadine compared with placebo for fever on day 3 in children. The review found no RCTs in elderly people. Categorisation unchanged (Likely to be ineffective or harmful).

BMJ Clin Evid. 2009; 2009: 0911.
Published online 2009 March 12.

Rimantadine (oral) to treat influenza

Summary

DURATION OF SYMPTOMS Compared with placebo: Oral rimantadine may be more effective at reducing the duration of fever ( very low-quality evidence ). NOTE There is consensus that rimantadine should not be used as first-line treatment, because cross-resistance to amantadine is high, and rimantadine is only effective against influenza A. We found no direct information about oral rimantadine versus placebo for the treatment of influenza A in children or in elderly people.

Benefits

We found two systematic reviews. The first systematic review (reported in two publications; search date 2005, 4 RCTs, 152 otherwise healthy people) compared oral rimantadine versus placebo in people with laboratory-confirmed influenza A. It found that rimantadine significantly reduced the duration of fever (by 1 day) compared with placebo, but there was no significant difference in nasal viral shedding at 2–5 days from the start of treatment (see table 9 and table 12 ). We found no RCTs examining the effect of rimantadine in preventing serious complications of influenza, such as pneumonia, exacerbation of chronic diseases, or complications in pregnancy. The second review (search date July 2007) found no RCTs in the elderly or children comparing rimantadine versus placebo.

Harms

The first review found insufficient evidence to assess the adverse effects of rimantadine versus placebo in adults with influenza A.The second review reported that rimantadine is associated with a harms such as tinnitus, hyperactivity, diarrhoea, and dizziness in children and the elderly. However, the review did not separate results between treatment and prohylaxis.

Comment

In vitro studies have found that rimantadine has specific antiviral activity against influenza A, but not influenza B viruses. Viruses resistant to rimantadine show cross-resistance to amantadine, and vice versa.

Clinical guide:

All trials included in the systematic review were in people with influenza infection confirmed by laboratory findings, and reporting and starting treatment within 48 hours of symptom onset. It is questionable whether such evidence is relevant to everyday practice, when patients present with influenza-like illness symptoms of variable duration, possibly caused by various different agents. There is insufficient evidence to comment on the effects of rimantadine in a pandemic or serious epidemic scenario, but its inability to diminish or suppress nasal excretion of viruses raises serious doubts as to its ability to suppress transmission.

Substantive changes

Rimantadine (oral) to treat influenza One systematic review added comparing rimantadine versus placebo in children and elderly people. It found no RCTs. There is consensus that rimantadine should not be used as first-line treatment, because cross-resistance to amantadine is high, and it is only effective against influenza A. Categorisation changed (from Likely to be ineffective or harmful to Trade-off between benefits and harms).


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